Equine motor neuron disease (EMND) is a neurodegenerative disorder of the horse characterized by progressive weakness, fasciculations, muscle wasting, and weight loss. Histopathological findings in the brain stem and spinal cord studies reveal that the weakness and muscle wasting result from degeneration of motor neurons in these tissues. The nature and the distribution of the neurodegenerative changes in EMND are strikingly similar to those reported in human progressive muscular atrophy, a form of amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease. As in ALS, the cause(s) of this disease is not known. The long-term objective of our research is to understand the pathogenesis of this disease so that effective control measures can be recommended to prevent its occurrence. We believe that findings on this equine disorder can help to uncover the causative factor(s) for sporadic ALS. Our epidemiologic studies to date have implicated oxidative stress in the risk of EMND and have suggested that some intrinsic factors, e.g. disruption of the blood-brain-barrier, may influence the risk. We hypothesize that the blood-brain barrier (BBB), normally innocuous, can be disrupted as a result of the oxidative stress, exposing the central nervous system to exogenous, highly detrimental substances (i.e. neurotoxic). The proposed studies are aimed to test this hypothesis. We are planning to carry out two randomized trials to evaluate this hypothesis in rats. In the first trial two groups of rats will be identified and allocated randomly to either treatment or control group. The treatment group will receive a diet deficient in vitamin E and the control will receive a normal diet. The two groups will be followed up for a period of time and the permeability of the BBB will be assessed and compared in the two groups. In the second trial the impact of neurotoxic drugs on the risk of neurologic disorder in rats fed diet deficient in antioxidants will be assessed. The treatment group will receive ivermectin and the control group will not. The risk of neurologic disorder will then be assessed in the two groups. In the third hypothesis we will investigate whether the permeability of the BBB is disrupted in horses afflicted with EMND. Data obtained from these pilot studies will represent a major breakthrough towards the understanding of the mechanism of the motor neuron disease and lay the foundation for more thorough investigation.